Hormone refractory prostate cancer is currently incurable and is a main cause of death among prostate cancer patients, often emerging after androgen ablation therapy - a process that antagonizes androgen receptor (AR) transcriptional activity. AR is a nuclear transcription factor whose activity is determined by the coactivators and corepressors it assembles on the promoters of AR regulated genes. There are abundant data that demonstrate the importance of AR coactivators in prostate cancer. Previously we showed that NCoR (nuclear receptor corepressor) represses agonist and antagonist dependent transcription repression of AR. We found that AR corepressor NCoR is necessary for the response of prostate cancer cells to antiandrogen bicalutamide. Prostate cancer cell line proliferation and motility was not repressed by the bicalutamide in the absence of NCoR. Using Affimetrix microarrays we determined that depletion of NCoR expression in LNCap prostate cancer cells dramatically affected the expression of downstream targets of AR, leading to activation of AKT and PCDH11 pathways. Using human prostate tissue microarrays we found that NCoR is highly expressed in human prostate and its expression is significantly reduced in prostate cancer. We found significant correlation between downregulation of NCoR in prostate cancer and increased phosphorylation of the Akt. The development of the mouse prostate is strictly androgen dependent and, like the human prostate, it expresses high levels of NCoR. Our main hypothesis is that reduction in NCoR will result in increased proliferation of the prostate epithelium cells, androgen independence, and ultimately in malignant transformation similar to human prostate cancer. Specifically in this application we propose to: 1) test the hypothesis that NCoR is required for turnover and maintenance of normal prostate epithelium. We will test this hypothesis by creating mutant mice with targeted ablation of the NCoR gene in prostate using Cre/loxP recombinant technology. 2) determine if prostate-specific ablation of NCoR will lead to malignant transformation and increased AR signaling. We will determine if NCoR is required for the prostate response to androgen ablation. This will be accomplished by comparing responses to androgen ablation of normal mice and mice that have NCoR depleted in their prostates. The new NCoR mutant mice will represent an in vivo model for hormone-refractory androgen independent prostate cancer. It will allow us to understand how AR response to agonists and antagonists changes in prostate cancers that no longer express NCoR providing novel therapeutic targets. It will also allow us to determine if growth inhibitory properties of anti-androgens are dependent on NCoR expression and will provide a basis for future screening of anti-androgen compounds efficient in the absence of NCoR. PUBLIC HEALTH RELEVANCE: Androgen-independent recurrent cancer is currently incurable. We found that NCoR protein is required for the success of anti-androgen treatment. Using prostate cancer samples from over 400 patients we discovered significant decrease in the level of NCoR in prostate cancers compared to normal prostate tissue. We propose here to create a mouse model that would lack NCoR in prostate in order to understand the mechanism of anti-androgen resistance. This transgenic mouse can be used to search for new treatments for androgen-independent prostate cancer.